Methods of treating fibromyalgia syndrome, chronic fatigue syndrome and pain

ABSTRACT

The present invention provides a method of treating fibromyalgia syndrome (FMS), chronic fatigue syndrome (CFS), and pain in an animal subject. The method generally involves administering a therapeutically effective amount of a dual serotonin norepinephrine reuptake inhibitor compound or a pharmaceutically acceptable salt thereof, wherein said dual serotonin norepinephrine reuptake inhibitor compound is characterized by a non-tricyclic structure and an equal or greater inhibition of norepinephrine reuptake than serotonin reuptake. In particular, the use of milnacipran to treat FMS, CFS, and pain is disclosed.

This application is a divisional of U.S. Ser. No. 10/028,547 filed Dec.19, 2001, now U.S. Pat. No. 6,602,911, entitled “Methods of TreatingFibromyalgia Syndrome, Chronic Fatigue Syndrome and Pain” by Jay D.Kranzler and Srinivas G. Rao, which is a continuation-in-part of U.S.Ser. No. 10/014,149 filed Nov. 5, 2001, now U.S. Pat. No. 6,635,675.

1. FIELD OF THE INVENTION

The present invention relates to methods for the treatment offibromyalgia syndrome, chronic fatigue syndrome, and pain. Inparticular, the present invention relates to methods of treatingfibromyalgia syndrome, chronic fatigue syndrome, and pain with asub-class of dual serotonin norepinephrine reuptake inhibitorscharacterized by a non-tricyclic structure and inhibit the reuptake ofnorepinephrine to an equal or greater extent than they inhibit thereuptake of serotonin.

2. BACKGROUND OF THE INVENTION

Fibromyalgia syndrome (FMS) is the most frequent cause of chronic,widespread pain, estimated to affect 2–4% of the population. FMS ischaracterized by a generalized heightened perception of sensory stimuli.Patients with FMS display abnormalities in pain perception in the formof both allodynia (pain with innocuous stimulation) and hyperalgesia(increased sensitivity to painful stimuli). The syndrome, as defined bythe American College of Rheumatology's criteria, involves the presenceof pain for over 3 months duration in all four quadrants of the body, aswell as along the spine. In addition, pain is elicited at 11 out of 18“tender points” upon palpation. Other associated symptoms includefatigue, nonrestorative sleep, and memory difficulties.

Chronic fatigue syndrome (CFS) is a debilitating disorder characterizedby profound tiredness or fatigue. Patients with CFS may become exhaustedwith only light physical exertion, and must often function at a level ofactivity substantially lower than their capacity before the onset ofillness. In addition to the key defining characteristic of fatigue, CFSpatients generally report various nonspecific symptoms, includingweakness, muscle aches and pains, excessive sleep, malaise, fever, sorethroat, tender lymph nodes, impaired memory and/or mental concentration,insomnia, and depression. Like patients with FMS, patients with CFSsuffer from disordered sleep, localized tenderness, and complaints ofdiffuse pain and fatigue.

There are two widely used criteria for diagnosing CFS. The criteriaestablished by the U.S. Centers for Disease Control and Preventioninclude medically unexplained fatigue of at least six months durationthat is of new onset, not a result of ongoing exertion and notsubstantially alleviated by rest, and a substantial reduction inprevious levels of activity. In addition, the diagnosis involves thedetermination of the presence of four or more of the followingsymptoms—subjective memory impairment, tender lymph nodes, muscle pain,joint pain, headache, unrefreshing sleep, and postexertional malaise(>24 hours). Reid et al., 2000, British Medical Journal 320: 292–296.The diagnostic criteria from Oxford includes severe, disabling fatigueof at least six months duration that affects both physical and mentalfunctioning and the fatigue being present for more than 50% of the time.In addition, the diagnosis involves the determination of the presence ofother symptoms, particularly myalgia and sleep and mood disturbance.Reid et al., 2000, British Medical Journal 320: 292–296.

Owing to their common symptomology, FMS and CFS are thought to berelated. However, they manifest different major symptoms. Whereas painis the major symptom reported by patients with FMS, fatigue is the majorsymptom reported by patients with CFS. Given their relatedness, thesetwo indications have been treated with the same medications. Some of thecommon medications currently employed to treat CFS and/or FMS include,but are not limited to, analgesics, hypnotics, immune suppressants,various other prescribed medications, and an array of non-prescriptionmedications. Although a broad array of medications are used in FMS andCFS patients, no single pharmacological agent or combination of agentsis effective in the treatment of either of these disorders. Thus, due tothe lack of effective treatment regimens for FMS and/or CFS, there is aneed to develop effective treatments.

Pain is associated with a variety of different underlying illnesses orinjuries. Pain may be either acute or chronic. Chronic or intractablepain is often endured over many years or decades. Patients sufferingfrom chronic pain often develop emotional problems which can lead todepression and in the worst case, attempted suicide. Long lasting painoften occurs particularly in joints, in muscles, connective tissue andin the back. In the United States alone, chronic pain causes a loss ofmore than 250 million working days per year. A patient is considered tohave chronic pain when complaints thereof last longer than six months.In the course of time, chronic pain may form an independent clinicalsyndrome.

Most analgesic agents in use today are not always effective, may produceserious side effects and can be addictive. Hence, there is a demand formore active analgesic agents with diminished side effects and toxicity,and which are non-addictive. The ideal analgesic would reduce theawareness of pain, produce analgesia over a wide range of pain types,act satisfactorily whether given orally or parenterally, produce minimalor no side effects, and be free from the tendency to produce toleranceand drug dependence.

3. SUMMARY OF THE INVENTION

In one aspect, the invention provides a method of treating fibromyalgiasyndrome (FMS) and/or the symptoms associated therewith in an animalsubject, including a human. The method generally involves administeringto an animal subject suffering from FMS an effective amount of a dualserotonin norepinephrine reuptake inhibitor (“SNRI”) compound of aspecific type, or a pharmaceutically acceptable salt thereof. The SNRIcompounds that are useful to treat FMS and/or symptoms associatedtherewith are characterized by a non-tricyclic structure and inhibit thereuptake of norepinephrine to an equal or greater extent than theyinhibit the reuptake of serotonin (referred to hereinafter as “NE≧5-HTSNRI compounds”). In one embodiment of the invention, the NE≧5-HT SNRIcompound administered inhibits norepinephrine reuptake to a greaterdegree than it inhibits serotonin reuptake (referred to hereinafter as a“NE>5-HT SNRI compound”). One particular example of such a NE>5-HT SNRIcompound is milnacipran, or a pharmaceutically acceptable salt thereof.In another embodiment, the NE≧5-HT SNRI compound is not administeredadjunctively with phenylalanine, tyrosine and/or tryptophan.

In another aspect, the invention provides a method of treating pain inan animal subject, including a human. The method generally involvesadministering to an animal subject suffering from pain an effectiveamount of a NE≧5-HT SNRI compound, or a pharmaceutically acceptable saltthereof. In one embodiment, a NE>5-HT SNRI compound is administered. Oneparticular example of a NE>5-HT SNRI compound is milnacipran or apharmaceutically acceptable salt thereof. In another embodiment, theNE≧5-HT SNRI compound is not administered adjunctively withphenylalanine, tyrosine and/or tryptophan.

In still another aspect, the invention provides a method of treating CFSand/or symptoms associated therewith. The method generally involvesadministering to a patient suffering from CFS an effective amount of aNE≧5-HT SNRI compound, or a pharmaceutically acceptable salt thereof. Inone embodiment, a NE>5-HT SNRI compound is administered. One particularexample of a NE>5-HT SNRI compound is milnacipran or a pharmaceuticallyacceptable salt thereof. In another embodiment, the NE≧5-HT SNRIcompound is not administered adjunctively with phenylalanine, tyrosineand/or tryptophan.

In yet another aspect, the invention provides a kit comprising a NE≧5-HTSNRI compound packaged in association with instructions teaching amethod of using the compound according to one or more of theabove-described methods. The kit can contain the NE≧5-HT SNRI compoundpackaged in unit dosage form. In one embodiment, a NE>5-HT compound canbe included in the kit. One particular example of a NE>5-HT SNRIcompound is milnacipran or a pharmaceutically acceptable salt thereof.

4. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

4.1 Abbreviations

-   CFS chronic fatigue syndrome-   FMS fibromyalgia syndrome-   5-HT serotonin-   NARIs norepinephrine specific reuptake inhibitors-   NE norepinephrine-   NMDA N-methyl D-aspartate-   NSAIDs non-steroidal anti-inflammatory drugs-   SSRIs selective serotonin reuptake inhibitors-   TCAs tricyclic antidepressants-   SNRIs dual serotonin norepinephrine reuptake inhibitors

4.2 Definitions

The term “dual serotonin norepinephrine reuptake inhibitor compound” orSNRI refers to the well-recognized class of anti-depressant compoundsthat selectively inhibit reuptake of both serotonin and norepinephrine.Common SNRI compounds include, but are not limited to, venlafaxine,duloxetine, and milnacipran.

The terms “NE≧5-HT SNRI” and “NE>5-HT SNRI” refer to particularsubclasses of SNRI compounds that are useful in the methods and kits ofthe present invention, as will be described in more detail herein.

4.3 Treatment of FMS, CFS and/or Pain

The present invention provides methods and kits for treating FMS, CFS,and pain. A particular subclass of SNRI compounds is useful forpracticing the present invention. Compounds in this SNRI subclass,referred to as “NE≧5-HT SNRI compounds,” inhibit norepinephrine reuptakemore than or equal to serotonin reuptake. Moreover, the NE≧5-HTcompounds of the invention exclude compounds that belong to the distinctclass of antidepressant compounds commonly referred to in the art astricyclic antidepressants or TCAs. In particular, compounds useful forpracticing the present invention inhibit norepinephrine reuptake morethan serotonin reuptake, referred to as “NE>5-HT SNRI compounds.”

Tricyclic antidepressants (TCAs) are a well-recognized class ofantidepressant compounds that are characterized by a dibenz[b,e]azepine(structure I), dibenz[b,e]oxepine (structure II),dibenz[a,d]cycloheptane (structure III) or dibenz[a,d]cycloheptene(structure IV) tricyclic ring structure. These various rings aredepicted below:

The TCAs are typically substituted at position 1 of the tricyclic ringwith alkylamines or alkylidenamines, and may include additionalsubstituents (typically on the benzo groups). Many common TCAs,including imipramine, desipramine, clomipramine, trimipramine,amitriptyline, nortriptyline, doxepin, cyclobenzaprine and protriptlineare characterized by the general formula (V), below:

wherein:

-   -   X is O or C;    -   Y is N or C;    -   R¹ is H or Cl;    -   R² is selected from the group consisting of —(CH₂)₃N(CH₃)₂,        —(CH₂)₃NHCH₃, —CH₂CH(CH₃)CH₂N(CH₃)₂, ═CH(CH₂)N(CH₃)₂,        ═CH(CH₂)₂NHCH₃ and —(CH₂)₃NHCH₃; and    -   the dotted line represents a single bond or a double bond.        The NE≧5-HT SNRI compounds of the invention exclude compounds        classified as tricyclic antidepressants, and thus exclude        compounds characterized by the above-depicted fused tricyclic        nuclei of structures (I), (II), (III), and (IV).

As mentioned above, the NE≧5-HT SNRI compounds useful in the methods andkits of the invention include compounds that inhibit norepinephrinereuptake to a greater extent than serotonin reuptake, as well ascompounds that inhibit the reuptake of these two monoamines to anequivalent extent. In one embodiment of the invention, the NE≧5-HT SNRIcompounds have a ratio of inhibition of norepinephrine reuptake toserotonin reuptake (“NE:5-HT”) in the range of about 1–100:1. In aparticular embodiment, the compounds are NE>5-HT SNRI compounds, i.e.,compounds that inhibit norepinephrine reuptake to a greater extent thanserotonin reuptake. Such NE>5-HT SNRI compounds generally have a NE:5-HTin the range of about 1.1–100:1. That is, such NE>5-HT SNRI compoundsare at least 1.1 to about 100 times more effective at inhibitingnorepinephrine reuptake than serotonin reuptake. NE>5-HT SNRI compoundshaving a NE:5-HT ratio in the range of about 2:1 to about 10:1 may beparticularly effective.

Various techniques are known in the art to determine the NE:5-HT of aparticular SNRI. In one embodiment, the ratio can be calculated fromIC₅₀ data for NE and 5-HT reuptake inhibition. For example, it has beenreported that for milnacipran the IC₅₀ of norepinephrine reuptake is 100nM, whereas the IC₅₀ serotonin reuptake inhibition is 200 nM. See Moretet al., 1985, Neuropharmacology 24(12):1211–1219; Palmier et al., 1989,Eur J Clin Pharmacol 37:235–238. Therefore, the NE:5-HT reuptakeinhibition ratio for milnacipran based on this data is 2:1. Of course,other IC values such as IC₂₅, IC₇₅, etc. could be used, so long as thesame IC value is being compared for both norepinephrine and serotonin.The concentrations necessary to achieve the desired degree of inhibition(i.e., IC value) can be calculated using known techniques either in vivoor in vitro. See Sanchez et al., 1999, Cellular and MolecularNeurobiology 19(4):467–489; Turcotte et al., 2001,Neuropsychopharmacology 24(5):511–521; Moret et al. 1985,Nueropharmacology 24(12):1211–1219; Moret et al., 1997, J. Neurochem.69(2): 815–822; Bel et al., 1999, Neuropharmacology 21(6):745–754; andPalmier et al., 1989, Eur J Clin Pharmacol 37:235–238.

The NE:5-HT of a particular SNRI also can be calculated usingequilibrium dissociation constants (K_(D)'s) for norepinephrine andserotonin transporters as described in Tatsumi et al., 1997, EuropeanJournal of Pharmacology 340:249–258. For example, a NE>5-HT SNRIcompound with a K_(D) of 2 nM for the norepinephrine transporter and aK_(D) of 8 nM for the serotonin transporter has an NE:5-HT of 4:1.

Yet another means for determining the NE:5-HT of a particular SNRIinvolves measuring the affinity (K_(i)) of the SNRI for thenorepinephrine and serotonin transporters as described in Owens et al.,1997, JPET 283:1305–1322. For example, a NE>5-HT SNRI compound with aK_(i) of 1 nM for the norepinephrine transporter and a K_(i) of 20 nMfor the serotonin transporter has an NE:5-HT of 20:1.

A specific example of a NE≧5-HT SNRI compound that can be used topractice the present invention is milnacipran. Additional NE≧5-HT SNRIcompounds that can be used to practice the present invention include, byway of example and not limitation, any of the aminocyclopropanederivatives disclosed in the following references that inhibitnorepinephrine reuptake to an equivalent or greater extent thanserotonin reuptake (i.e., that have a NE:5-HT ratio that is ≧1:1):WO95/22521; U.S. Pat. No. 5,621,142; Shuto et al., 1995, J. Med. Chem.38:2964–2968; Shuto et al., 1996, J. Med. Chem. 39:4844–4852; Shuto etal., 1998, J. Med. Chem. 41:3507–3514; Shuto et al., 2001, Jpn. J.Pharmacol. 85:207–213; Noguchi et al., 1999, Synapse 31:87–96; and U.S.Pat. No. 4,478,836. All of these references are hereby incorporatedherein by reference in their entireties.

In a specific embodiment of the invention, the NE>5-HT SNRI compound ismilnacipran. The chemical structure of milnacipran,cis-(±)-2-(aminomethyl)-N,N-diethyl-1-phenyl-yclopropanecarboxamide, isas follows:

Milnacipran is also known in the art as F2207, TN-912, dalcipran,midalcipran, and midalipran. The NE:5-HT of milnacipran is 2:1. SeeMoret et al., 1985, Neuropharmacology 24(12):1211–1219; Palmier et al.,1989, Eur J Clin Pharmacol 37:235–238. Milnacipran and methods for itssynthesis are described in U.S. Pat. No. 4,478,836, which is herebyincorporated by reference in its entirety. Additional informationregarding milnacipran may be found in the Merck Index, 12^(th) Edition,at entry 6281. Quite significantly, milnacipran has been used as anantidepressant in approximately 400,000 patients, and is known to benon-toxic in humans. In clinical trials at dosages of 100 mg/day or 200mg/day, milnacipran was well tolerated and usually produced no moreadverse effects than placebo (Spencer and Wilde, 1998, Drugs56(3):405–427).

Those of skill in the art will recognize that NE≧5-HT SNRI compoundssuch as milnacipran may exhibit the phenomena of tautomerism,conformational isomerism, geometric isomerism and/or optical isomerism.It should be understood that the invention encompasses any tautomeric,conformational isomeric, optical isomeric and/or geometric isomericforms of the NE≧5-HT SNRI compounds having one or more of the utilitiesdescribed herein, as well as mixtures of these various different forms.For example, as is clear from the above structural diagram, milnacipranis optically active. It has been reported in the literature that thedextrogyral enantiomer of milnacipran is about twice as active ininhibiting norepinephrine and serotonin reuptake than the racemicmixture, and that the levrogyral enantiomer is much less potent (see,e.g., Spencer and Wilde, 1998, supra; Viazzo et al., 1996, TetrahedronLett. 37(26):4519–4522; Deprez et al., 1998, Eur. J. Drug Metab.Pharmacokinet. 23(2):166–171). Accordingly, milnacipran may beadministered in entantiomerically pure form (e.g., the pure dextrogyralenantiomer) or as a mixture of dextogyral and levrogyral enantiomers,such as a racemic mixture. Unless specifically noted otherwise, the term“milancipran” as used herein refers to both enantiomerically pure formsof milnacipran as well as to mixtures of milnacipran enantiomers.Methods for separating and isolating the dextro- and levrogyralenantiomers of milnacipran and other NE≧5-HT SNRI compounds arewell-known (see, e.g., Grard et al., 2000, Electrophoresis 200021:3028–3034).

It will also be appreciated that in many instances the NE≧5-HT SNRIcompounds may metabolize to produce active NE≧5-HT SNRI compounds. Theuse of active metabolites is also within the scope of the presentinvention.

It has been reported that milnacipran and its derivatives haveantagonistic properties at the NMDA receptor. See Shuto et al., 1995, J.Med. Chem. 38:2964–2968; Shuto et al., 1996, J. Med. Chem. 39:4844–4852;Shuto et al., 1998, J. Med. Chem. 41:3507–3514; and Shuto et al., 2001,Jpn. J. Pharmacol. 85:207–213. As a consequence, one particularly usefulembodiment of the invention includes NE≧5-HT SNRI compounds that alsohave NMDA antagonistic properties. The NE≧5-HT SNRI compounds with NMDAreceptor antagonistic properties can have IC₅₀ values from about 1nM–100 μM. For example, milnacipran has been reported to have an IC₅₀value of about 6.3 μM. The NMDA receptor antagonistic properties ofmilnacipran and its derivatives are described in Shuto et al., 1995, J.Med. Chem., 38:2964–2968; Shuto et al., 1996, J. Med. Chem.39:4844–4852; Shuto et al., 1998, J. Med. Chem. 41:3507–3514; and Shutoet al., 2001, Jpn. J. Pharmacol. 85:207–213. Methods for determining theantagonism and affinity for antagonism are disclosed in Shuto et al.,1995, J. Med. Chem. 38:2964–2968; Shuto et al., 1996, J. Med. Chem.39:4844–4852; Shuto et al., 1998, J. Med. Chem. 41:3507–3514; Noguchi etal., 1999, Synapse 31:87–96; and Shuto et al., 2001, Jpn. J. Pharmacol.85:207–213. Aminocyclopropane derivatives disclosed in WO95/22521; U.S.Pat. No. 5,621,142; Shuto et al., 1995, J. Med. Chem. 38:2964–2968;Shuto et al., 1996, J. Med. Chem. 39:4844–4852; Shuto et al., 1998, J.Med. Chem. 41:3507–3514; Noguchi et al., 1999, Synapse 31:87–96; andShuto et al., 2001, Jpn. J. Pharmacol. 85:207–213 that inhibit NEreuptake equal to or greater than 5-HT reuptake and have NMDAantagonistic properties can be used to practice the present invention.These references are hereby incorporated by reference in their entirety.

It has recently been reported that compounds that inhibit reuptake ofboth NE and 5-HT, such as venlafaxine, duloxetine, milnacipran, andcertain TCAs, are effective for the treatment of pain, CFS and FMS,among other maladies, when administered in combination withneurotransmitter precursors such as phenylalanine, tyrosine and/ortryptophan. See WO 01/26623. For example, according to one studyreported in WO 01/26623, a patient experiencing, inter alia, fatigue andfibromyalgia, was administered many types of drugs, including many typesof non-steroidal anti-inflammatories, both tricyclic and serotoninreuptake inhibiting and noradrenalin reuptake inhibitingantidepressants, and even steroids, without effect. When given acombination of lofepramine (70 mg. bd) and L-phenylalanine (500 mg. bd),the patient experienced a considerable improvement in fatigue andfibromyalgia, which persisted for more than six months. Thus, a compoundthat inhibits reuptake of both NE and 5-HT was effective only whenadministered in combination with a neurotransmitter precursor.

Quite surprisingly, the present inventors have discovered that theNE≧5-HT SNRI subclass of SNRI compounds are effective in treating CFS,FMS and pain when administered alone (or in combination with othercompounds that are not neurotransmitter precursors such asphenylalanine, tyrosine and/or tryptophan, as will be discussed in moredetail, below). Thus, in one embodiment of the invention, the NE≧5-HTSNRI compound is administered alone, or in combination with a compoundother than a neurotransmitter precursor such as phenylalanine, tyrosineand/or tryptophan.

The NE≧5-HT SNRI compounds, such as, for example, milnacipran, can beadministered adjunctively with other active compounds such asantidepressants, analgesics, muscle relaxants, anorectics, stimulants,antiepileptic drugs, and sedative/hypnotics. Specific examples ofcompounds that can be adjunctively administered with the NE≧5-HT SNRIcompounds include, but are not limited to, neurontin, pregabalin,pramipexole, 1-DOPA, amphetamine, tizanidine, clonidine, tramadol,morphine, tricyclic antidepressants, codeine, cambamazepine,sibutramine, amphetamine, valium, trazodone and combinations thereof.Typically for FMS patients the NE≧5-HT SNRI compounds may beadjunctively administered with antidepressants, anorectics, analgesics,antiepileptic drugs, muscle relaxants, and sedative/hypnotics. For CFSpatients, the NE≧5-HT SNRI compounds may be adjunctively administeredantidepressants, anorectics, stimulants, and sedative/hypnotics. Forpatients suffering from pain the NE≧5-HT SNRI compounds may beadjunctively administered with antidepressants, analgesics,antiepileptic drugs. By adjunctive administration is meant simultaneousadministration of the compounds, in the same-dosage form, simultaneousadministration in separate dosage forms, and separate administration ofthe compounds. For example, milnacipran can be simultaneouslyadministered with valium, wherein both milnacipran and valium areformulated together in the same tablet. Alternatively, milnacipran couldbe simultaneously administered with valium, wherein both the milnacipranand valium are present in two separate tablets. In another alternative,milnacipran could be administered first followed by the administrationof valium, or vice versa.

The NE≧5-HT SNRI compounds can be administered therapeutically toachieve a therapeutic benefit or prophylactically to achieve aprophylactic benefit. By therapeutic benefit is meant eradication oramelioration of the underlying disorder being treated, e.g., eradicationor amelioration of the underlying FMS, CFS or pain disorder, and/oreradication or amelioration of one or more of the physiological symptomsassociated with the underlying disorder such that the patient reports animprovement in feeling or condition, notwithstanding that the patientmay still be afflicted with the underlying disorder. For example,administration of milnacipran to a patient suffering from FMS providestherapeutic benefit not only when the underlying FMS indication iseradicated or ameliorated, but also when the patient reports decreasedfatigue, improvements in sleep patterns, and/or a decrease in theseverity or duration of pain.

Although depression is often comorbid in patients suffering from FMS andCFS, and could therefore be characterized as a symptom associated withthese disorders, it is well-recognized in the art that NE≧5-HT SNRIcompounds such as milnacipran are useful in the treatment of depression.Accordingly, while successful treatment regimens of the inventioncontemplate providing an improvement in at least one symptom associatedwith FMS or CFS, treatment regimens that cause an improvement only indepression are considered ineffective for purposes of the presentinvention. While improvements in associated psychological symptoms suchas depression may be reported, for purposes of the present invention, animprovement in the underlying disorder and/or in at least one of thephysiological symptoms associated with the disorder must be reported.Thus, the present invention does not contemplate the treatment ofdepression alone.

For therapeutic administration, the NE≧5-HT SNRI compound typically willbe administered to a patient already diagnosed with the particularindication being treated.

For prophylactic administration, the NE≧5-HT SNRI compound may beadministered to a patient at risk of developing FMS, CFS, or pain or toa patient reporting one or more of the physiological symptoms of FMS orCFS, even though a diagnosis of FMS or CFS may not have yet been made.Alternatively, prophylactic administration may be applied to avoid theonset of the physiological symptoms of the underlying disorder,particularly if the symptom manifests cyclically. In this latterembodiment, the therapy is prophylactic with respect to the associatedphysiological symptoms instead of the underlying indication. Forexample, the NE≧5-HT SNRI compound could be prophylacticallyadministered prior to bedtime to avoid the sleep disturbances associatedwith FMS or CFS. Alternatively, the NE≧5-HT SNRI compound could beadministered prior to recurrence of pain, or prior to onset of fatigue.

While the invention has been described so far with respect to NE≧5-HTSNRI compounds, the present invention can also be practiced withnorepinephrine specific reuptake inhibitors (NARIs). NARIs are awell-recognized class of compounds that specifically inhibit thereuptake of only norepinephrine. An example of a compound that isclassified as a NARI is reboxetine.

4.4 Formulation and Routes of Administration

The NE≧5-HT SNRI compounds useful in the present invention, orpharmaceutically acceptable salts thereof, can be delivered to a patientusing a wide variety of routes or modes of administration. Suitableroutes of administration include, but are not limited to, inhalation,transdermal, oral, rectal, transmucosal, intestinal and parenteraladministration, including intramuscular, subcutaneous and intravenousinjections.

The term “pharmaceutically acceptable salt” means those salts whichretain the biological effectiveness and properties of the compounds usedin the present invention, and which are not biologically or otherwiseundesirable. Such salts include salts with inorganic or organic acids,such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitricacid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid,acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid,malic acid, citric acid, tartaric acid or maleic acid. In addition, ifthe compounds used in the present invention contain a carboxy group orother acidic group, it may be converted into a pharmaceuticallyacceptable addition salt with inorganic or organic bases. Examples ofsuitable bases include sodium hydroxide, potassium hydroxide, ammonia,cyclohexylamine, dicyclohexyl-amine, ethanolamine, diethanolamine andtriethanolamine.

The compounds, or pharmaceutically acceptable salts thereof, may beadministered singly, in combination with other NE≧5-HT SNRI compounds,and/or in cocktails combined with other therapeutic agents. Of course,the choice of therapeutic agents that can be co-administered with thecompounds of the invention will depend, in part, on the condition beingtreated.

The active NE≧5-HT SNRI compounds (or pharmaceutically acceptable saltsthereof) may be administered per se or in the form of a pharmaceuticalcomposition wherein the active compound(s) is in admixture or mixturewith one or more pharmaceutically acceptable carriers, excipients ordiluents. Pharmaceutical compositions for use in accordance with thepresent invention may be formulated in conventional manner using one ormore physiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

For injection, the NE≧5-HT SNRI compounds may be formulated in aqueoussolutions, preferably in physiologically compatible buffers such asHanks's solution, Ringer's solution, or physiological saline buffer. Fortransmucosal administration, penetrants appropriate to the barrier to bepermeated are used in the formulation. Such penetrants are generallyknown in the art.

For oral administration, the compounds can be formulated readily bycombining the active compound(s) with pharmaceutically acceptablecarriers well known in the art. Such carriers enable the compounds ofthe invention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained as a solid excipient, optionally grinding aresulting mixture, and processing the mixture of granules, after addingsuitable auxiliaries, if desired, to obtain tablets or dragee cores.Suitable excipients are, in particular, fillers such as sugars,including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate.

Dragee cores can be provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

For administration orally, the compounds may be formulated as asustained release preparation. Numerous techniques for formulatingsustained release preparations are described in the followingreferences—U.S. Pat. Nos. 4,891,223; 6,004,582; 5,397,574; 5,419,917;5,458,005; 5,458,887; 5,458,888; 5,472,708; 6,106,862; 6,103,263;6,099,862; 6,099,859; 6,096,340; 6,077,541; 5,916,595; 5,837,379;5,834,023; 5,885,616; 5,456,921; 5,603,956; 5,512,297; 5,399,362;5,399,359; 5,399,358; 5,725,883; 5,773,025; 6,110,498; 5,952,004;5,912,013; 5,897,876; 5,824,638; 5,464,633; 5,422,123; and 4,839,177;and WO 98/47491. Specifically, sustained release formulations ofmilnacipran are described in WO 98/08495. These references are herebyincorporated herein by reference in their entireties.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For administration by inhalation, the active compound(s) may beconveniently delivered in the form of an aerosol spray presentation frompressurized packs or a nebulizer, with the use of a suitable propellant,e.g., dichlorodifluoromethane, trichlorofluoromethane,dicblorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof e.g. gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

Alternatively, the active compound(s) may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation or transcutaneous delivery (forexample subcutaneously or intramuscularly), intramuscular injection or atransdermal patch. Thus, for example, the compounds may be formulatedwith suitable polymeric or hydrophobic materials (for example as anemulsion in an acceptable oil) or ion exchange resins, or as sparinglysoluble derivatives, for example, as a sparingly soluble salt.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymerssuch as polyethylene glycols.

4.5 Effective Dosages

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredient is contained in atherapeutically or prophylactically effective amount, i.e., in an amounteffective to achieve therapeutic or prophylactic benefit, as previouslydiscussed. Of course, the actual amount effective for a particularapplication will depend, inter alia, on the condition being treated andthe route of administration. Determination of an effective amount iswell within the capabilities of those skilled in the art, especially inlight of the disclosure herein.

Therapeutically effective amounts for use in humans can be determinedfrom animal models. For example, a dose for humans can be formulated toachieve circulating concentration that has been found to be effective inanimals. Useful animal models of pain are well known in the art. Modelsof neuropathic pain are described in Zeltser et al., 2000, Pain89:19–24; Bennett et al., 1988, Pain 33:87–107; Seltzer et al., 1990,Pain 43:205–218; Kim et al., 1992, Pain 50:355–363; and Decosterd etal., 2000, Pain 87:149–158. An animal model of inflammatory pain usingcomplete Freund's adjuvant is described in Jasmin et al., 1998, Pain 75:367–382. The stress-induced hyperalgesia model described in Quintero etal., 2000, Pharmacology, Biochemistry and Behavior 67:449–458 may beused as an animal model of FMS and CFS.

Effective amounts for use in humans can be also be determined from humandata for the NE≧5-HT SNRI compounds used to treat depression. The amountadministered can be the same amount administered to treat depression orcan be an amount lower than the amount administered to treat depression.For example, the amount of milnacipran administered to treat depressionis in the range of about 50 mg–400 mg/day. Thus, either 50 mg–400 mg/dayor a lower dose can be administered for practicing the presentinvention.

Patient doses for oral administration of the NE≧5-HT SNRI compoundtypically range from about 1 μg–1 gm/day. For example, for the treatmentof FMS, CFS, or pain with milnacipran the dosage range is typically from25 mg–400 mg/day, more typically from 100 mg–250 mg/day. The dosage maybe administered once per day or several or multiple times per day. Theamount of the NE≧5-HT SNRI compound administered to practice methods ofthe present invention will of course, be dependent on the subject beingtreated, the severity of the affliction, the manner of administrationand the judgment of the prescribing physician. The dose used to practicethe invention can produce the desired therapeutic or prophylacticeffects, without producing serious side effects.

5. EXAMPLES 5.1 Example 1 Assessment of the Analgesic Properties ofMilnacipran in a Rat Pain Model

The rats used in this study are divided into two groups. One group ofrats receive a spinal ligation as described in Kim et al., 1992, Pain50(3):355–63 and the other group of rats receive a sham surgery. Eachgroup of rats is further divided into 5 subgroups. Each subgroupreceives subcutaneous injection of the vehicle or one of the 4 testdoses of milnacipran (5, 10, 25, and 50 mg/kg). The vehicle ormilnacipran are administered at a pre-determined time point followingthe surgeries. Allodynia and thermal hyperalgesia are respectivelymeasured with Von Frey filaments and tail or paw-flick with a radiantheat source. The allodynia and thermal hyperalgesia measurements areperformed at the following time points—prior to surgery, followingsurgery but prior to the administration of vehicle or milnacipran, andfollowing surgery after the administration of vehicle or milnacipran.The allodynia and thermal hyperalgesia measurements will provideinformation on the ability of milnacipran to block the development ofmechanical allodynia and thermal hyperalgesia.

5.2 Example 2 Assessment of the Efficacy of Milnacipran in an FMS AnimalModel

This study is performed on rats or mice that have undergonestress-induced hyperalgesia as described in Quintero et al., 2000,Pharmacology, Biochemistry and Behavior 67:449–458. The study consistsof 3 groups: placebo, milnacipran subcutaneous pretreatment, andmilnacipran treatment. The milnacipran groups are further divided to 4subgroups and each subgroup is administered 5, 10, 25, or 50 mg/kg ofmilnacipran. In the milnacipran subcutaneous pretreatment group, themilnacipran is administered prior to the inducement of thestress-induced hyperalgesia. In the milnacipran treatment group, themilnacipran is administered following the inducement of thestress-induced hyperalgesia. Allodynia and thermal hyperalgesia arerespectively measured with Von Frey filaments and tail- or paw-flickwith a radiant heat source. The allodynia and thermal hyperalgesiameasurements are performed at the following time points—prior to boththe inducement of stress-induced hyperalgesia and the administration ofthe milnacipran, prior to the inducement of stress-induced hyperalgesiabut following the administration of the milnacipran, following theinducement of stress-induced hyperalgesia but prior to administration ofthe milnacipran, following both the inducement of stress-inducedhyperalgesia and the administration of the milnacipran. The allodyniaand thermal hyperalgesia measurements provide information on whetherpretreatment or treatment with milnacipran will be effective in thetreatment of stress-induced thermal and mechanical hyperalgesia.

5.3 Example 3 Assessment of the Efficacy of Milnacipran in FMS Patients

Approximately 40 subjects are studied for a total of 6 weeks, afterbeing weaned from their previous analgesic or antidepressantmedications.

The inclusion criteria for this study is as follows:

-   -   1. Patients meet the 1990 American College of Rheumatology        criteria for fibromyalgia syndrome.    -   2. Male or female between the ages of 18 and 70 years. Females        are either postmenopausal (no menses for at least 1 year) or        status-post oophorectomy (bilateral) or have a negative        pregnancy test and be using an accepted method of contraception.    -   3. Patients have a Gracely intensity pain scale recording        (weekly recall) of at least 10 or more on a 20 point scale at        baseline.    -   4. Patients may use non-prescription doses of NSAIDs, aspirin        and acetaminophen on a PRN basis for acute pain unrelated to        their underlying fibromyalgia.

The patients are divided into 2 groups. The first group is administered100 mg of milnacipran in a single-dose in the morning, while the secondgroup is administered 50 mg twice a day (i.e., upon awakening and priorto going to sleep). Each patient is then followed for 6 weeks, withvisits every two weeks, as follows:

As indicated above, global patient (Pt) and physician (MD) assessmentsare taken at the beginning and end of the trial. In addition, a total of4 sets of pain and sleep measures are also performed at 2-weekintervals. The pain measure consists of the patient's recall of overallpain over the previous 2-week period as indicated by a 10 cm visualanalog scale. The sleep instrument consists of 4 questions taken fromthe Jenkin's sleep questionnaire. It is expected that milnacipran willproduce an improvement in a majority of the patients.

5.4 Example 4 Assessment of the Efficacy of Milnacipran in Patients withPainful Diabetic Neuropathy

20 patients with painful diabetic neuropathy (DN) are studied in adouble-blind cross-over study. The inclusion criteria for the studyare—age of between 18 and 85 years, daily pain of at least “moderateintensity” on the Gracely scale for greater than three months that waspresent more than 50% of the day, and adequate communication abilitydemonstrated during a telephone conversation and by completion of a paindiary. Additional inclusion criteria are a diagnosis of diabetes, anddistal, symmetrical diabetic neuropathy as assessed by either anunequivocal decrease in pinprick, temperature, or vibration sense inboth feet or ankles or decreased or absent ankle jerk reflexes.Exclusion criteria are the presence of another more painful condition,difficulty with ambulation, any unstable disease process, a history ofsignificant substance abuse or alcoholism, liver or kidney disease, orconcurrent use of a monoamine oxidase inhibitor.

Milnacipran is compared to placebo in a randomized, double-blind,two-period, crossover study. After discontinuing other medication forpain for two weeks, patients enter a one-week baseline period, followedby two six-week drug treatment periods, separated and concluded by aone-week washout period. The treatments, given in random order, aremilnacipran titrated up to maximum-tolerated dose or placebo. A nursecalls the patients every three days to titrate medication dosage and toassess pain, side effects, and study compliance. During the first fourweeks of each period (titration phase) the medication is increased by 25mg/day every three days unless the patient reports complete pain relief,side effects that interfere with daily activities, or unless the maximumdose of 200 mg daily is reached. During weeks 5 and 6 (maintenancephase), the highest well-tolerated dose is maintained at a constantlevel.

Prior to randomization, a general physical exam and laboratory tests(complete blood count, liver function tests, blood glucose, hemoglobinA1c, blood urea nitrogen, creatinine, electrolytes and urinalysis) isobtained. Diabetics are examined to assure they had adequate blood sugarcontrol before and during the trial. They are instructed to performdaily blood sugar monitoring using a fingerstick and a home glucometer.In addition, a neurologic examination is performed at baseline toidentify any area of increased pain to pinprick (hyperalgesia),decreased sensation to pinprick, or pain with stimulation by cottongauze (allodynia); these studies are conducted every 2 weeks during thetrial. In addition, patients record their pain intensity in a diary 3times daily using the Gracely scale. It is expected that milnacipranwill produce an improvement in the majority of patients, as measured byboth physician neurological exam and patient diary.

Each of the patent applications, patents, publications, and otherpublished documents mentioned or referred to in this specification isherein incorporated by reference in its entirety, to the same extent asif each individual patent application, patent, publication, and otherpublished document was specifically and individually indicated to beincorporated by reference.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1. A method of treating pain in an animal subject, comprisingadministering to an animal subject suffering from pain, an effectiveamount of milnacipran, or a pharmaceutically acceptable salt thereof,alone or in combination with a compound that is not phenylalanine,tyrosine or tryptophan.
 2. The method according to claim 1, wherein thecompound is adjunctively administered with antidepressants, analgesics,muscle relaxants, anorectics, stimulants, antiepileptic drugs,sedatives, or hypnotics.
 3. The method according to claim 1, wherein thecompound is adjunctively administered with neurontin, pregabalin,pramipexole, 1-DOPA, amphetamine, tizanidine, clonidine, tramadol,morphine, a tricyclic antidepressant, codeine, carbamazepine,sibutramine, valium, or trazodone.
 4. The method according to claim 1,wherein the animal subject is human.
 5. The method according to claim 1,wherein the amount administered is from about 25 mg to about 400 mg perday.
 6. The method according to claim 1, wherein the compound isformulated in a sustained release dosage formulation.